Synthesis of pantothenic acid



Patented Mar. 20, 1945 UNITED STATES PATENT orncEi- SYNTHESIS OFPANTOTHENIC ACID Dilworth Wayne Woolley, New York, 'N.-Y., assignor toNational Oil Products Company, Harrison, N; 1., acorporation of NewJersey No -Drawing. Application July 30, 1940.

, Serial No. 348,451 1 7 Claims- (01.260-534) The present inventionrelates to the so-called chick antidermatitis factor and particularly tothe synthesis of this factor which has now been designated aspantothenic acid. 7 The "chick antidermatitis factor" and pantothenicacid have now been found to be the same chemical compound. This recentlydiscovered vitamin plays an important role in the growth of variousliving creatures; the absence of which in the diet results in dermatitisand other disorders. In a chick, for example, the absence of pantothenicacid in its diet causes fissures to develop. around its beak and eyes.It has been firmly established that pantothenic acid is necessary in theproper nutrition of chickens, rats, dogs, sheep and other livingcreatures.

Pantothenic acid has been found to exist in The general object of theinvention is to provide a process of synthesizing pantothenic acid. Aspecific object of the invention is to produce pantothenic acid at areasonable cost and in a purified state. 4

Another object of the invention involves the preparation of newcompounds useful inthe synthesis of pantothenic acid.

Other objects of the invention will in part be obvious and will in partappear hereinafter.

In accordance with its broader aspects, the in vention comprises aprocess involving" the con-- densation of an a]! diacyloxy pp. dimethyibutyryl halide with a suitable derivative of p alanine. Thecondensation: of compounds of the 'aforementioned type is preferablycarried on without the aid of heat and in the presence or not of asuitable solvent; preferably an alkyl ester oi p alanine is used in thecondensation step, such as' the methyl, ethyl, propyl or other suitableester of p alanine. The invention further contemplates the preparationof new chemical compounds developed in the synthesis of pantothenicacid. Such new compounds include the saltor halide of asyl-v me atdihydroxy pp dimethyl butyric acid, as

well as the product produced by the condensation of an ester'of palanine with a halide of acylated a-y dihydroxy pp dimethyl butyricacid. .In the preparation of an my diacyloxy flfl dimethyl butyrylhalide, it is preferable to start with a hydroxy fifl dimethyl 1 butyryllactone, which is a readily available compound. .Suitable derivatives ofthis lactone must be made, however, in

order to first free the 7 hydroxyl group and sub- 10 'sequently blockthe hydroxy groups so that the proper condensation with p alanine may beobtained. This is achieved by first forming a salt of a hydroxyppdimethyl 'y butyryl lactone. In the formation of this salt, which servesto free the 7 hydroxyl group, any suitable alkaline agent maybe used,such as sodium hydroxide, barium hydroxide, potassium hydroxide, calciumhy-' droxide, alkali carbonates and thelike. In order to block thehydroxyl groups, the foregoing salt is treated with an aliphatic acidanhydride such,

-for example, as acetic anhydride, propionic anhydride and the like, theuse of acetic anhydride being preferred.

The invention accordingly comprises the several steps and relation ofone or more of such steps with respect to each of theothers, and theproducts possessing the features, properties and the relation ofelements, which are exemplified lnthe followingdetailed disclosure, andthe scope of the invention will be indicated in the claims.

' More specifically, in carrying out theprocess of the invention, it ispreferred to commence the synthesis of pantothenic acid with a hydroxypp dimethyl j-y butyryl lactone which has the follow- 85 ing structuralformula:

cm on o c -l i The foregoing lactone is preferably treated with a onenormal solution of sodium hydroxide and the mixture evaporated todryness, whereupon the sodium salt of a7 dihydroxy fifl dimethyl butyricacid is formed. While sodium hydroxide is preferred in this step, it isobvious that any other suitable base may be employed,,including, amongothers,-pots.ssium, barium and cal- .cium hydroxides, alkali carbonates,etc.

The next step in the synthesis involves the conversion of the hydroxylgroups of the original acid into acyl groups by treatment of the saltwith an aliphatic acid anhydride, prefer ably acetic anhydride. A'largeexcess of the acetic anhydrideis addedtothe salt; after which 2 p themixture is heatedand evaporated to dryness, preferably under. reducedpressure, thus forming the sodium salt of my diacetoxy pp dimethyibutyric acid, which has the following structural formula:

. CH: H

While it is believed that the anhydride reacts with both the hydroxylgroups, it may be that only the '7 hydroxyl group is reacted, wherebythe a hydroxyl group remains intact If the a hydroxyl group is notreacted with the anhydride, it will not react with any of the otherreagents used in the process to interfere with the desired synthetic endproduct.

The foregoing compound is next treated with a suitable agent to convertthe salt into a halide.

In this operation thionyl chloride is permitted to stand for a whilewith the foregoing acetoxy The foregoing compound is now admixed with analkyl ester of n alanine, whereby the chloride combines with a hydrogen*atom of the amino group of ,3 alanine toaccomplish the amide linkagebetween the m7 diacetoxy fifl dimethyl butyryl chloride and the ,3alanine alkyl ester. The condensation is preferably carried out at roomtemperature or slightly below (10 to 20 C.) and is usually completed inabout one hour. In order to neutralize the'HCl given of! during thecondensation, a suitableamount of pyridine may, be'provided in themixture or an excessof the p alanine ester may be provided. Likewise, Pyidine, ether or the like my be used as a solvent during the condensationwhich proceeds as follows:

winte -enrollment to a pH value of about 1.5 to 2.5, after which.

the same is extracted with a suitable solvent such as ethyl acetate, theresulting solvent solution of the condensation product is thenevaporated to dryness.

The foregoing condensation product is freed of its acetoxy groups andthe ester group by treatment with a 10% solution of sodium hydroxide inabsolute alcohol. Any suitable base may be used in this saponiflcationprocess, it being necessary,

- however, to use a substantially anhydrous reagent as the condensationproduct will not tolerate much more thah about 2% water in the mixture;10%

procedure which is carried out at room temperature or slightly less thanroom temperature,

' mineral acid such as hydrochloric acid and the product filtered,evaporated to dryness under vacuum and extracted with absolute alcohol,whereby pantothenic acid having the following structural formularesults! It has been found that the salt of pantothenic acid is equallyas active as pantothenic acid itself; furthermore, the preparation anduse of the salt itself is preferred in view of its greater chemicalstability. Moreover, any salt of pantothenic acid may be preparedaccording to the process of the invention and used as such; these saltsinclude, among others, the alkali metal,

ammonium and alkaline earth salts.

Since certain changes'in carrying out the above process and certainmodifications in the product which embody the invention may be madewithout departing from its scope, it is intended that all mattercontained in the above sodium hydroxide in absolute ethanol is highlypreferred in the saponification description shall be interpreted asillustrative and not in a limiting sense.

Having described my invention, what I claim as new anddesire to secureby Letters Patent, is: a

1. In the process of synthesizing the chick antidermatitis factor, thestep which comprises condensing an my diacyloxy pp dimethyl butyrylhalide with an alkyl ester of o alanine.

2. In the process of synthesizing the chick antidermatitisfactor, thestep which comprises con- In the event thatan excess of the ,8 alaninedensing a7 diacetoxy mo dimethyl butyryl chloride with-an alkyl ester of,8 alanine.

8. A process of synthesizing the chick antidermatitis factor, whichcomprises condensing an 017 diacyloxy pp dimethyl butyryl halide with analkyl ester of p alanine and saponifying all the ester linkages in thecondensation product.

4. A process of synthesizing the chick antidermatitis factor, whichcomprises condensing a'y diacetoxy pp dimethyl butyryl chloride with analkyl ester of ,3 alanine and saponifying all the ester linkages in thecondensation product.

EA process of synthesizing the chick an hydroxy BB dimethyl 1 butyryllactone with an inorganic alkaline agent to form a salt thereof,reacting said salt with an aliphatic acid anhydride, halogenating theacylated product. condensing said product with an alkyl ester of palanine and saponifying all the ester linkages in the condensationproduct. l W

6. A process of synthesizing the chick antider- -matitis factor, whichcomprises treating a hy-' dermatitis factor, which omprises treating a'I. In the process of the chick antidermatitis Iactonthe step whichcomprises con-' densing an alkyl ester of p alanine with a chemicalcompound selected from the class having the following general formula:

on, in

wherein A represents an acetoxy group, A! represents a member selectedfrom the group consist-'- ing or acetoxy and hydroxyl groups and Xrepresents a halogen atom.

4 nmwoa'rn warm: wooLLnY.

